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Immuno-PET Molecular Imaging of RANKL in Cancer

1
Molecular Imaging Center Antwerp (MICA), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
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Nuclear Medicine, Antwerp University Hospital, Drie Eikenstraat 655, B-2650 Edegem, Belgium
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Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium
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Laboratory of Pathological Anatomy, Antwerp University Hospital, Drie Eikenstraat 655, B-2650 Edegem, Belgium
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Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Drie Eikenstraat 655, B-2650 Edegem, Belgium
*
Author to whom correspondence should be addressed.
Academic Editor: Antonia Dimitrakopoulou-Strauss
Cancers 2021, 13(9), 2166; https://doi.org/10.3390/cancers13092166
Received: 22 March 2021 / Revised: 26 April 2021 / Accepted: 27 April 2021 / Published: 30 April 2021
Receptor activator of the nuclear factor kappa B ligand (RANKL) has been recently identified as a target of interest in the tumor microenvironment (TME), specifically in facilitating an immunosuppressive environment and subsequent resistance to immunotherapy. However, assessment of RANKL in the TME remains difficult due to its heterogeneous nature and suboptimal sampling methods. In our study we developed an anti-RANKL immuno-PET tracer to non-invasively monitor RANKL expression in the TME and help to understand the RANK/RANKL pathway.
Purpose: The involvement of RANK/RANKL signaling in the tumor microenvironment (TME) in driving response or resistance to immunotherapy has only very recently been recognized. Current quantification methods of RANKL expression suffer from issues such as sensitivity, variability, and uncertainty on the spatial heterogeneity within the TME, resulting in conflicting reports on its reliability and limited use in clinical practice. Non-invasive molecular imaging using immuno-PET is a promising approach combining superior targeting specificity of monoclonal antibodies (mAb) and spatial, temporal and functional information of PET. Here, we evaluated radiolabeled anti-RANKL mAbs as a non-invasive biomarker of RANKL expression in the TME. Experimental design: Anti-human RANKL mAbs (AMG161 and AMG162) were radiolabeled with 89Zr using the bifunctional chelator DFO in high yield, purity and with intact binding affinity. After assessing the biodistribution in healthy CD-1 nude mice, [89Zr]Zr-DFO-AMG162 was selected for further evaluation in ME-180 (RANKL-transduced), UM-SCC-22B (RANKL-positive) and HCT-116 (RANKL-negative) human cancer xenografts to assess the feasibility of in vivo immuno-PET imaging of RANKL. Results: [89Zr]Zr-DFO-AMG162 was selected as the most promising tracer for further validation based on biodistribution experiments. We demonstrated specific accumulation of [89Zr]Zr-DFO-AMG162 in RANKL transduced ME-180 xenografts. In UM-SCC-22B xenograft models expressing physiological RANKL levels, [89Zr]Zr-DFO-AMG162 imaging detected significantly higher signal compared to control [89Zr]Zr-DFO-IgG2 and to RANKL negative HCT-116 xenografts. There was good visual agreement with tumor autoradiography and immunohistochemistry on adjacent slides, confirming these findings. Conclusions: [89Zr]Zr-DFO-AMG162 can detect heterogeneous RANKL expression in the TME of human cancer xenografts, supporting further translation of RANKL immuno-PET to evaluate tumor RANKL distribution in patients. View Full-Text
Keywords: RANKL; antibody; PET; tumor microenvironment RANKL; antibody; PET; tumor microenvironment
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MDPI and ACS Style

Dewulf, J.; Vangestel, C.; Verhoeven, Y.; De Waele, J.; Zwaenepoel, K.; van Dam, P.A.; Elvas, F.; Van den Wyngaert, T. Immuno-PET Molecular Imaging of RANKL in Cancer. Cancers 2021, 13, 2166. https://doi.org/10.3390/cancers13092166

AMA Style

Dewulf J, Vangestel C, Verhoeven Y, De Waele J, Zwaenepoel K, van Dam PA, Elvas F, Van den Wyngaert T. Immuno-PET Molecular Imaging of RANKL in Cancer. Cancers. 2021; 13(9):2166. https://doi.org/10.3390/cancers13092166

Chicago/Turabian Style

Dewulf, Jonatan, Christel Vangestel, Yannick Verhoeven, Jorrit De Waele, Karen Zwaenepoel, Peter A. van Dam, Filipe Elvas, and Tim Van den Wyngaert. 2021. "Immuno-PET Molecular Imaging of RANKL in Cancer" Cancers 13, no. 9: 2166. https://doi.org/10.3390/cancers13092166

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